The pentapeptide known as methionine-enkephalin, H-Tyr-Gly-Gly-Phe-Met-OH, is one of a family of peptides recently isolated from brain and pituitary extracts which are able to bind specifically to brain opiate receptor sites and which appear to be derived from a C-terminal portion of beta-lipotropin. Evidence is mounting that one or more of these compounds are the components of a central pain suppressive system, particularly since at least two of the peptides exert analgesic effects when injected intraventricularly. The object of this research would be to carry out the synthesis and evaluate some biological and behavioral properties of peptides closely related to the enkephalins, which are the smallest active sequences. In this way we would hope to develop analogs with much increased binding affinity and analgesic activity. Preliminary work indicates that the stabilization of a proposed beta-bend conformation centered around the first glycine residue is one possible approach to the problem. The development of a long-sought, non-tolerance inducing, non-addictive analgesic would also clearly require the synthesis of peptides with prolonged biological half-life and the ability to cross the blood-brain barrier after systemic administration. The preparation of the C61-91 fragment of beta-lipotropin would be undertaken in order to allow a radioimmunoassay measurement method to be set up for this, the most potent peptide of the enkephalin series. The establishment of a sound synthetic route would also enable structure-activity work to proceed on this large peptide. Structure-activity work and biological evaluation on the recently discovered 61-76 and 61-77 lipotropin fragments known as alpha-endorphin and gamma-endorphin, respectively, would also be carried out.